Harish G. Ahuja

Randomized, Double-Blinded Phase II Evaluation of Docetaxel with or without Doxercalciferol in Patients with Metastatic, Androgen-Independent Prostate Cancer

Purpose: Docetaxel is standard of care for androgen-independent prostate cancer (AIPC). Doxercalciferol (1α-hydroxyvitamin D2) had modest activity in phase I/II trials. Preclinical data support combining vitamin D analogues with docetaxel to treat AIPC. Experimental Design: Chemotherapy-naive men with metastatic AIPC were randomized 1:1 to receive, on a 4-week cycle, docetaxel (35 mg/m2 i.v., days 1, 8, and 15) with or without doxercalciferol (10 μg orally, days 1-28). The primary end point was prostate-specific antigen (PSA) response. Secondary end points were progression-free survival, overall survival, objective response, and toxicity. Survival was analyzed as intent to treat. Results: Seventy patients were randomized. Median follow-up was 17.6 months (range, 3.3-45.2). PSA response rate was 46.7% [95% confidence interval (95% CI), 30-64] in the doxercalciferol arm and 39.4% (95% CI, 25-56) with placebo (P = 0.560). Median progression-free survival in the doxercalciferol arm was 6.17 months (95% CI, 4.20-10.7) versus 6.20 months (95% CI, 4.83-9.07) with placebo (P = 0.764). Median overall survival in the doxercalciferol arm was 17.8 months (95% CI, 14.9-23.6) versus 16.4 months (95% CI, 11.9-23.8) with placebo (P = 0.383). Twenty-four patients in the doxercalciferol arm and 23 in the placebo arm were evaluable for objective response. No complete responses were observed. Partial objective response rate was 12.5% with doxercalciferol versus 8.7% with placebo (P = 0.672). Rate of grade ≥3 toxicity was 46% with doxercalciferol versus 42% with placebo (P = 0.785). Conclusions: Daily doxercalciferol with weekly docetaxel did not enhance PSA response rate or survival. Toxicity was similar between arms. Despite the disappointing results of this study, other vitamin D analogues remain under active investigation.

Phase II study of arsenic trioxide and ascorbic acid for relapsed or refractory lymphoid malignancies: a Wisconsin Oncology Network study†

Arsenic trioxide (As2O3) has established clinical activity in acute promyelocytic leukaemia and has pre‐clinical data suggesting activity in lymphoid malignancies. Cell death from As2O3 may be the result of oxidative stress. Agents which deplete intracellular glutathione, such as ascorbic acid (AA), may potentiate arsenic‐mediated apoptosis. This multi‐institution phase II study investigated a novel dosing schedule of As2O3 and AA in patients with relapsed or refractory lymphoid malignancies. Patients received As2O3 0.25 mg/kg IV and AA 1000 mg IV for five consecutive days during the first week of each cycle followed by twice weekly infusions during weeks 2–6. Cycles were repeated every 8 weeks. The primary end point was objective response. In a subset of patients, sequential levels of intracellular glutathione and measures of Bcl‐2 and Bax gene expression were evaluated in peripheral blood mononuclear cells during treatment. Seventeen patients were enrolled between March 2002 and February 2004. The median age was 71, and the majority of enrolled patients had non‐Hodgkins lymphoma (12/17). Sixteen patients were evaluable, and one patient with mantle cell lymphoma achieved an unconfirmed complete response after five cycles of therapy for an overall response rate of 6%. The trial, which had been designed as a two‐stage study, was closed after the first stage analysis due to lack of activity. Haematologic toxicities were the most commonly reported events in this heavily pre‐treated population, and comprised the majority of grade 3 and 4 toxicities. Intracellular depletion of glutathione was not consistently observed during treatment. As2O3 and AA in this novel dosing strategy was generally well tolerated but had limited activity in patients with relapsed and refractory lymphoid malignancies. Copyright

A phase 2 study of weekly temsirolimus and bortezomib for relapsed or refractory B-cell non-Hodgkin lymphoma: A Wisconsin Oncology Network study

Proteasome inhibitors and mammalian target of rapamycin inhibitors each have activity in various B‐cell malignancies and affect distinct cellular pathways. Their combination has demonstrated synergy in vitro and in mouse models.

A Phase II Trial of Gemcitabine, 5-Fluorouracil and Leucovorin in Advanced Esophageal Carcinoma

Background: The aim of this study was to evaluate the overall response rate, toxicity and overall survival in patients with locally advanced or metastatic esophageal cancer treated with gemcitabine, 5-fluorouracil (5-FU) and leucovorin. Patients and Methods: Patients with either adenocarcinoma or squamous cell carcinoma of the esophagus could enroll; however, patients could not have received prior chemotherapy for metastatic disease. Treatment cycles consisted of infusions of all three agents at days 1, 8 and 15, repeated every 28 days. Patients received gemcitabine 1,000, leucovorin 25 and 5-FU 600 mg/m2. Tumor assessment was performed every 2 cycles. Responses were assessed using the Eastern Cooperative Oncology Group solid tumor response criteria. Results: Thirty-five patients with metastatic or locally advanced esophageal cancer enrolled. One complete response and ten partial responses were observed for an overall response rate of 31.4%. An additional 11 patients had stable disease as their best response. The median survival was 9.8 months with a 1-year survival rate of 37.1%. Toxicity was predominately hematologic, with 58% of patients experiencing grade 3 or 4 neutropenia. Conclusion: The combination of gemcitabine, 5-FU and leucovorin had activity in advanced esophageal cancer. Patients tolerated the regimen well, with myelosuppression occurring most commonly. The combination merits further investigation as a treatment for esophageal cancer.

Phase I/II Study of Gemcitabine and Exisulind as Second-Line Therapy in Patients with Advanced Non–small Cell Lung Cancer

Background: The study was designed to evaluate the safety and efficacy of exisulind, a selective apoptotic antineoplastic drug, in combination with gemcitabine as second-line therapy in patients with progressing advanced non–small cell lung cancer. Methods: Patients whose disease progressed more than 3 months from completion of first-line chemotherapy were eligible for this phase I/II trial. Primary end points were maximally tolerated dose and time to progression. Patients in the phase I portion of the study were treated with gemcitabine (1250 mg/m2) in combination with three escalated dose levels of exisulind. Treatment involved six cycles of gemcitabine and exisulind followed by exisulind maintenance. The study was subsequently expanded to phase II. Results: Thirty-nine patients (15 in phase I and 24 in phase II) were treated. The regimen was well tolerated with grade 3 fatigue and grade 3 constipation being dose-limiting toxicities. The maximally tolerated dose was not reached. Dose level 3 of exisulind (250 mg twice daily) in combination with gemcitabine was used for phase II. The overall response rates were 7% (phase I), 17% (phase II), and 13% (all). Median time to progression and median and 1-year survival, respectively, were 3.7 and 9.7 months and 33% (phase I); 4.3 and 9.4 months and 41% (phase II); and 4.1 and 9.4 months and 39% (all). Conclusion: Although the study met its primary end point of improving time to progression (more than 4.1 months in phase II), we did not observe a clear survival advantage and thus do not plan to further investigate this schedule of gemcitabine and exisulind.

Phase I/II Study of Vinorelbine and Exisulind as First-Line Treatment of Advanced Non-small Cell Lung Cancer in Patients at Least 70 Years Old: A Wisconsin Oncology Network Study

Introduction: Exisulind is an apoptotic agent with preclinical activity in non-small cell lung cancer (NSCLC). Vinorelbine is safe and effective in older patients with advanced NSCLC. We assessed these agents together as palliative treatment for older patients with advanced NSCLC. Methods: Chemotherapy-naive patients ≥70-years-old with stage IIIB-IV NSCLC and a performance status (PS) ≤2 were eligible. Primary endpoints were the maximum tolerated dose (phase I) and time-to-progression (phase II) of oral exisulind with 25 mg/m2/wk of intravenous vinorelbine on a 28-day cycle. Patients with clinical benefit after 6 cycles of this combination received exisulind alone. Results: Fourteen phase I patients (median PS 1; median age 78 years) were enrolled. Dose-limiting toxicities included grade 3 constipation (one patient), grade 3 febrile neutropenia (one patient) and grade 3 diarrhea (one patient). The maximum tolerated dose of oral exisulind with 25 mg/m2/wk of intravenous vinorelbine was 125 mg twice daily. Thirty phase II patients (median PS 1; median age 78 years) were enrolled. Grade ≥3 neutropenia occurred in 14/30 patients. Two patients experienced neutropenic fever. There were no complete responses, one partial response and 12 patients with stable disease as their best response. The objective response rate was 4.0% (95% CI: 0.1-20.4%). Phase II median time-to-progression was 4.7 months (95% CI: 3.1-9.3 months) and median OS was 9.6 months (95% CI: 6.6-19.1 months). Conclusions: This combination is safe, seems to have activity in the elderly with advanced NSCLC and a PS ≤2, and warrants further investigation.

Phase I/II study of exisulind and gemcitabine in patients with recurrent advanced non-small cell lung cancer (NSCLC)

7103 Background: Exisulind is an oral selective apoptotic antineoplastic drug which inhibits the cyclic GMP phosphodiesterase. The combination of exisulind and gemcitabine produced an additive anti-tumor effect in preclinical studies. The objectives of this study were to determine the maximally tolerated dose (MTD) (Phase I) and clinical efficacy (Phase II) of this combination in patients (pts) with recurrent advanced NSCLC. METHODS In phase I, exisulind was escalated in 3 dose levels (from 125mg BID up to 250mg BID) in combination with a fixed dose of gemcitabine 1250mg/m2 IV days 1 and 8 of a 3 week cycle. Plan for phase II is to accrue 24 pts (95% power to detect a 50% increase in TTP from 3 months to 4.5 months with the level of significance of 0.1). Eligibility: Disease recurrence of more than 3 months from completion of first-line therapy, only one prior chemotherapy regimen, PS 0-1. RESULTS To date, 33 pts (24men, 9 women) have been enrolled; 15 in phase I and 18 in phase II. Median age was 65. 30% had PS 0, 70% had PS 1. 60% had distant metastasis. All pts received platinum-based doublets as first-line therapy, of which 94% were third-generation regimens. Phase I: Six pts were entered to dose level 1, 3 in dose level 2 and 6 in dose level 3. Of 14 evaluable pts, 1 achieved PR, while 4 had SD after 6 cycles of treatment. The regimen was well tolerated (MTD not reached) with grade 3 fatigue and grade 3 constipation being DLTs (1 patient each). Myelotoxicities were mild. Phase II (ongoing): Dose level 3 was chosen for testing. Of 18 pts, 7 have died, 11 survived including 4 who are still on treatment. PR was seen in 2/18 pts, SD in 10/18. Toxicities included G3/4 leukopenia in 4 pts (22 %), G3/4 neutropenia 7 (39 %), G3 neutropenic infection 1 (6%), G3 anemia 2 (11 %), G3 thrombocytopenia 3 (17 %), G3 transaminases 3 (17 %). As of 8/03, of 32 evaluable pts enrolled in both phase I/II, disease was controlled in 17 pts (53%) including 3 with PR (9 %) and 14 with SD (44 %). Median and one year survival was 10 months and 40% (standard error 13%) in phase I. CONCLUSIONS The study regimen is well tolerated and the phase I results are promising. Phase II is still ongoing; survival and TTP will be updated. [Table: see text].